Inflammation is a biological response that can result from a noxious stimulus and is normally intended to remove that stimulus or ameliorate its effects. Although normally intended to promote survival, inflammation can cause damage to the host, especially in mammals. The stimulus or insult initiating inflammation can be caused by endogenous factors (e.g., an auto-antigen or irritating body fluid) or exogenous factors (e.g., a foreign body or infectious agent).
Inflammation has been classified as “acute” and “chronic.” Acute inflammation is typically of relatively short duration, lasting minutes to hours and, in some cases, a few days. Acute inflammation can be characterized by the exudation of fluid and plasma proteins and the accumulation of polymorphonuclear leukocytes (PMNLs) at the site of the insult. Acute inflammation usually includes an increase in blood flow to the area of the insult mediated by cellular molecules released in response to the insult. Increased vascular permeability also results from cellular mediators and leads to an accumulation of protein-rich fluid. Important mediators of this increased blood flow and vascular permeability include histamine from mast cells, serotonin and bradykinin.
In acute inflammation, PMNLs are also attracted to the area of insult and migrate out of the blood stream toward the insult. The PMNLs release toxic metabolites and proteinases that can cause tissue damage. These proteinases include proteins in the complement system, which can damage cell membranes and kallikreins which generate bradykinin. Acute inflammation can undergo complete resolution, lead to the formation of an abscess, result in scarring fibrosis or progress to chronic inflammation.
Chronic inflammation is of longer duration, lasting weeks to months, and possibly years, in which tissue destruction and biological processes that are intended to repair the injury are simultaneously ongoing. Chronic inflammation more typically involves lymphocytes and macrophages and may also include a proliferation of blood vessels, fibrosis and/or necrosis. Chronic inflammation can result from a number of conditions including persistent infections, prolonged exposure to toxic agents, and autoimmune reactions. Chronic inflammation is often maintained by the production of cytokines by lymphocytes and macrophages at the site of the persistent insult. Chronic inflammation can result in permanent tissue damage or complete healing.
Hypersensitivity generally refers to inflammation that causes damage to the host, in which the damage outweighs the benefit to the host. Hypersensitivity can result in significant pathology including, e.g., anaphylaxis, transplant rejection, and autoimmune diseases. The most common type of hypersensititvity is allergy.
Independently of the inducing factor—and the length of the exposure—an inflammatory reaction is mediated by a varied number and type of cells and molecules, the later including cytokines, growth factors, clotting factors, enzymes, neurotransmitters and complement proteins, among others. These molecules are primarily secreted by fibroblasts, endothelial and infiltrating cells (e.g. macrophages, lymphocytes, mast cells, polymorphonuclear cells, etc), and local nerves in response to the insulting agent. The mixture and amount of cytokines therein released will depend on the type, concentration and exposure time of the inducing agent. Therefore, these proteins could mediate from an acute local inflammatory reaction to systemic life-threatening responses (e.g. acute systemic inflammatory response syndrome, SIRS; multiple organ failure as in septic shock; anaphylaxis, etc). In chronic inflammatory processes, the cytokines continuously recruit more and more infiltrating cells that generate, for example, granulomas, induration of the tissues, and encapsulated abscesses. In any case, proteins secreted during an inflammatory process are central players in the grade and persistence of the final reaction.
Stimulation of the aforementioned cells by the induction agent leads to a cascade of intracellular signaling events that ultimately result in production and secretion of cytokines and other inflammatory mediators that constitute the pro-inflammatory response. While the pro-inflammatory response is crucial for effective clearance of the pathogen or allergen, the inflammatory mediators produced cause tissue damage and inflammation. Hence, a balance needs to be maintained between the activation and down-regulation of this response in order to avoid severe tissue damage (Cohen, J.: The immunopathogenesis of sepsis. Nature 2002 420, 885-891). Dysregulation of this response could induce local damage (e.g. lung fibrosis) or could lead to potentially lethal conditions like septic shock and systemic inflammatory response syndrome (SIRS) as previously mentioned. Thus, microbes allergens, endotoxins, and many other molecules induce the production of pro-inflammatory mediator proteins by different cells in the human body. The combined effects of all these molecules in living tissues could mediate changes in the clotting system, wound healing process, anti-microbial activity, antibody production and the perception of pain, among many other reactions.
The systemic inflammatory response syndrome (SIRS), a syndrome that encompasses the features of systemic inflammation without end-organ damage or identifiable bacteremia. SIRS is separate and distinct from sepsis, severe sepsis or septic shock. The key transition from SIRS to sepsis is the presence of an identified pathogen in the blood. The pathophysiology of SIRS includes, but is not limited to, complement activation, cytokine and arachidonic acid metabolites secretion, stimulated cell-mediated immunity, activation of the clotting cascades, and humoral immune mechanisms. Clinically SIRS is characterized by tachycardia, tachypnea, hypotension, hypoperfusion, oliguria, leukocytosis or leukopenia, pyrexia or hypothermia, metabolic acidosis, and the need for volume support. SIRS may affect all organ systems and may lead to multiple organ dysfunction syndrome (MODS). Thus, even in early stages (i.e. SIRS), there is accumulation of pro-inflammatory cytokines at the primary site of inflammation and in the blood that can contribute to the establishment of multi-organ failure and death.
Typically, inflammation is treated with steroidal or non-steroidal anti-inflammatory drugs. However, conventional anti-inflammatory therapy suffers from several drawbacks, e.g., systemic toxicity, allergic reactions, insulin resistance, hypertension, cardiac toxicity, renal toxicity, various coagulopathies and gastric erosions. Accordingly, there is a need for mild, yet safe and effective methods for treating or preventing inflammation.
The present invention provides such methods. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.